Association between chronic kidney disease stages and changes in ambulatory blood pressure monitoring parameters

Abstract Introduction: Blood pressure (BP) assessment affects the management of arterial hypertension (AH) in chronic kidney disease (CKD). CKD patients have specific patterns of BP behavior during ambulatory blood pressure monitoring (ABPM). Objectives: The aim of the current study was to evaluate the associations between progressive stages of CKD and changes in ABPM. Methodology: This is a cross-sectional study with 851 patients treated in outpatient clinics of a university hospital who underwent ABPM examination from January 2004 to February 2012 in order to assess the presence and control of AH. The outcomes considered were the ABPM parameters. The variable of interest was CKD staging. Confounding factors included age, sex, body mass index, smoking, cause of CKD, and use of antihypertensive drugs. Results: Systolic BP (SBP) was associated with CKD stages 3b and 5, irrespective of confounding variables. Pulse pressure was only associated with stage 5. The SBP coefficient of variation was progressively associated with stages 3a, 4 and 5, while the diastolic blood pressure (DBP) coefficient of variation showed no association. SBP reduction was associated with stages 2, 4 and 5, and the decline in DBP with stages 4 and 5. Other ABPM parameters showed no association with CKD stages after adjustments. Conclusion: Advanced stages of CKD were associated with lower nocturnal dipping and greater variability in blood pressure.

Introduction: Blood pressure (BP) assessment affects the management of arterial hypertension (AH) in chronic kidney disease (CKD).CKD patients have specific patterns of BP behavior during ambulatory blood pressure monitoring (ABPM).Objectives: The aim of the current study was to evaluate the associations between progressive stages of CKD and changes in ABPM.Methodology: This is a cross-sectional study with 851 patients treated in outpatient clinics of a university hospital who underwent ABPM examination from January 2004 to February 2012 in order to assess the presence and control of AH.The outcomes considered were the ABPM parameters.The variable of interest was CKD staging.Confounding factors included age, sex, body mass index, smoking, cause of CKD, and use of antihypertensive drugs.Results: Systolic BP (SBP) was associated with CKD stages 3b and 5, irrespective of confounding variables.Pulse pressure was only associated with stage 5.The SBP coefficient of variation was progressively associated with stages 3a, 4 and 5, while the diastolic blood pressure (DBP) coefficient of variation showed no association.SBP reduction was associated with stages 2, 4 and 5, and the decline in DBP with stages 4 and 5. Other ABPM parameters showed no association with CKD stages after adjustments.Conclusion: Advanced stages of CKD were associated with lower nocturnal dipping and greater variability in blood pressure.

IntRoductIon
The prevalence of arterial hypertension (AH) is high 1 .This clinical condition compromises the heart, blood vessels, brain, and kidneys 2 .Chronic kidney disease (CKD) prevalence in Brazil is estimated at around 10% of the population 2 , of which approximately 150,000 are in the most advanced progressive stage, requiring dialysis 3 .
AH is highly prevalent in CKD 4 .The pathophysiological link between AH and CKD is well known, with AH being the major risk factor for CKD in Brazil 3 .Hypertension and kidney injury establish a cycle of cause and consequence that worsens the prognosis 5 .Among the pathophysiological characteristics of AH in CKD, we could mention sodium retention, sympathetic hyperactivity, and hyperactivity of the renin-angiotensinaldosterone system 6 .These particularities are associated with characteristics of blood pressure (BP) behavior and its circadian pattern 7 .
Thus, BP control is crucial as it reduces structural and functional damage to nephrons and improves the life expectancy of patients with kidney disease 6 .This emphasizes the importance of accurate BP assessment in CKD.Defining the type of AH as normotension, true hypertension, white-coat hypertension, and masked hypertension is paramount for patient management 8 .
Ambulatory blood pressure monitoring (ABPM) is the best available means of assessing patients' BP over a 24-hour period in the clinic [8][9][10][11][12] .CKD patients have specific patterns of BP behavior over a 24-hour period, including reduced nocturnal dipping or even increased BP during sleep.
Some studies have evaluated these patterns; however, they are still scarce.A meta-analysis 13 identified only 6 studies [14][15][16][17][18][19] that assessed the prevalence of white-coat hypertension and masked hypertension in chronic kidney disease patients.This meta-analysis identified a high prevalence of masked hypertension and white-coat hypertension in CKD patients.However, among the analyzed studies, the most significant one had included only 290 patients 15 .It is important to note that these studies did not consider confounding variables.
We did not identify any studies on ABPM specific alterations in CKD that separately evaluated each progressive stage of the disease, compared them with control groups without CKD, or performed statistical adjustments for confounding variables.
Therefore, the aim of the current study was to assess the associations between progressive stages of CKD and changes in ABPM, considering confounding variables.

methods
In this cross-sectional study, we analyzed 851 patients from the cardiology, endocrinology, internal medicine and nephrology outpatient clinics at Hospital das Clínicas, Botucatu Medical School.These patients underwent ABPM testing from January 2004 to February 2012, which is recommended for diagnostic assessment and control of AH 20 .The majority of patients were on drug treatment, and this was considered in the statistical analyses.
The outcomes considered were the following ABPM parameters: the average of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP); nighttime SBP and DBP dipping percentage; BP variability; AH phenotype (normotension, sustained hypertension, white-coat hypertension and masked hypertension).The variable of interest is CKD staging.We considered confounding factors: age, sex, body mass index (BMI), smoking, and cause of CKD.
Inclusion criteria comprised patients aged 18 years and older who underwent ABPM during the study period.The exclusion criteria were: patients who underwent technically inadequate ABPMs according to the V Brazilian Guidelines for Ambulatory Blood Pressure Monitoring and Home Blood Pressure Monitoring Guidelines; pregnant women; kidney transplant recipients; patients with Parkinson's disease; patients with atrial fibrillation; incomplete ABPM data; repeated tests; and lack of data to establish the CKD stage.
Office SBP and DBP obtained immediately before the ABPM examination were recorded.Creatinine levels and urine tests conducted within a maximum of 3 months before or after the ABPM were recorded.Glomerular filtration rate (GFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
ABPM tests were performed using the Spacelabs ® 90202.ABPM was standardized based on the V Brazilian Guidelines for Ambulatory Blood Pressure Monitoring (ABPM) and the III Guidelines for Home Blood Pressure Monitoring 21 .The average SBP and DBP were recorded via software over the entire examination, during wakefulness and sleep period.SBP and DBP dipping during the sleep period were calculated.Blood pressure variability was quantified by the standard deviation of pressures, as well as by the coefficient of variation.
This study complies with the Strobe Statement 22 , and with Resolution 466/12 of the National Health Council, which is compatible with the Declaration of Helsinki.The local research ethics committee also approved it.Informed consent was waived.

defInItIons
We used the following as a definition for white-coat hypertension: office blood pressure greater than or equal to 140/90 mmHg and ABPM measurements during daytime period less than or equal to 135/85 mmHg.In light of the new considerations of the VI Brazilian Guidelines for Ambulatory Blood Pressure Monitoring (ABPM) 23 , nighttime BP was also considered.Thus, the definition included a 24-hour BP average greater than or equal to 130/80 mmHg.
The definition of masked hypertension used was: office BP less than 140/90 mmHg and ABPM measurements during awake hours greater than or equal to 135/85 mmHg.Given the new considerations of the VI Brazilian Guidelines for Ambulatory Blood Pressure Monitoring 23 , BP during sleep hours was also considered.Therefore, the definition included BP in the sleep period greater than or equal to 120/70 mmHg.
Sustained hypertension was defined when office BP was greater than or equal to 140/90 mmHg and daytime ABPM measurements were greater than or equal to 135/85 mmHg; whereas normotension was defined when office BP was less than 140/90 mmHg and daytime ABPM measurements were less than 135/85 mmHg.The data were also reanalyzed following the VI Brazilian Guidelines for Ambulatory Blood Pressure Monitoring 23 .
CKD was defined by KDIGO 2012 24 as a glomerular filtration rate lower than 60 mL/min/1.73m 2 , or the presence of proteinuria for more than 3 months.Additionally, CKD was classified based on its etiology and the GFR.

stAtIstIcAl AnAlysIs
Categorical data were expressed as absolute numbers and frequencies.Non-categorical variables with normal distribution were expressed as mean ± standard deviation.Data normality was confirmed using the Kolmogorov-Smirnov test.Continuous variables with normal distribution were compared using one-way ANOVA.Continuous variables with non-Gaussian distributions were subjected to the Kruskal-Wallis test.Categorical variables were compared using the χ 2 test.The multiple generalized linear regression model was applied to the variable of interest, as well as to the following confounding factors: age, sex, BMI, smoking, cause of CKD and number of antihypertensive drug classes.Data were discussed considering the significance level of p < 0.05.

Results
A total of 1,308 ABPM exams were performed over the study period.Of these, 52 were excluded as they failed to meet the technical conditions for validating the procedure.In addition, 92 patients were under 18 years of age, 18 were kidney transplant patients and 149 were repeated examinations, which were also excluded.Finally, an additional 146 patients were excluded due to incomplete creatinine data or urine test results.Thus, 851 patients were included in the analyses (Figure 1).Age was 55 ± 16.2 years; 42.4% were male; 6.6% were Afro-descendants; Asians and Caucasians accounted for 0.9% and 92.5%, respectively.Out of 682 patients, 74 (10.9%) were active smokers, while 156 (22.9%) were former smokers.
As for CKD staging, 376 out of 851 patients did not have CKD.Among the 475 CKD patients, 45 were in stage G1; 54 in stage G2; 97 in stage G3a; 89 in stage G3b; 71 in stage G4; and 119 were in stage G5 (Table 1).
Chronic kidney disease staging was associated with age (p < 0.001), male sex (p = 0.01), diabetes (p < 0.001) and dyslipidemia (p < 0.001).Ethnicity, BMI (p = 0.344), and smoking (p = 0.059) had no statistically significant association with CKD progression (Table 1), but were included in the multiple analysis model.The median and interquartile range of the number of antihypertensive classes used at each stage are depicted in Figure 2.
By means of ABPM, it was possible to observe the following distribution of hypertension phenotypes: 230 were normotensive; 140 had masked hypertension; 134 had white-coat hypertension; 347 were true hypertensives (Table 2).Abbreviations -CKD: chronic kidney disease; BMI: body mass index; *(%) = positive cases/total cases with available data (%).Regarding BP differences across the progressive stages of CKD (Table 2), there was a progressive elevation in office SBP with the progression of the kidney disease (p = 0.007).However, office DBP was not associated with CKD progression (p = 0.156).Except for the coefficient of variation of 24-hour DBP and DBP standard deviation, we observed an association between different stages of CKD progression and worsening of ABPM test parameters.There was an association between hypertension phenotypes and the stage of CKD for white-coat hypertension and sustained hypertension.The accuracy of office blood pressure was not associated with more advanced stages of CKD (Table 2).
By performing generalized linear regressions, we obtained a number of associations between CKD stage and ABPM test results adjusted for confounding variables: sex, smoking, dyslipidemia, diabetes, age, and number of antihypertensive drug classes.Systolic blood pressure on ABPM was associated with CKD stages 3a and 5, regardless of the confounding variables included in the model (Table 3).There was a decrease in the 24-hour SBP value for stage 3b, while an increase in its value was observed for stage 5.The decrease in diastolic blood pressure on ABPM was associated only with stage 3b.The increase in 24-hour PP on ABPM showed a statistically significant association with stage 5 CKD, irrespective of the adjustment variables (Table 3).
An increase in the coefficient of variation of 24-hour SBP was associated with stages 3a, 4 and 5 of CKD in the regressions, even considering the other confounding variables.Nevertheless, the coefficient of variation of 24-hour DBP on ABPM was not associated with any stage of CKD (Table 4).Finally, regarding BP dipping over the course of examination: decreased SBP dipping were independently associated with stages 2, 4 and 5.However, a reduced value for DBP dipping was only associated with the two most advanced stages of CKD (Table 4).

dIscussIon
This study examined the association between CKD stages and abnormalities observed in ABPM.It was possible to note that more advanced stages of CKD were progressively associated with lower nocturnal dipping and greater variability in blood pressure.24-hour SBP and 24-hour PP were associated with a more advanced level of CKD (stage V).The distinctive feature of the current study is that all these associations were seen regardless of sex, age, smoking, diabetes, and even the number of antihypertensive drug classes.
A cross-sectional study with 10,271 hypertensive patients revealed that the pulse pressure of those with chronic kidney disease was significantly higher compared to the PP of hypertensive individuals without kidney disease 7 .In this study, the most significant difference between the two groups investigated was the prevalence of the "riser" pattern (17.6% in CKD patients vs. 7.1% in non-CKD patients), i.e.where the average of nighttime systolic blood pressure is higher than the average of systolic blood pressure during awake hours.These data are consistent with those of the current study; however, this cross-sectional study did not adjust for confounding variables such as sex, age, smoking, and the presence of diabetes.
Agarwal & Andersen 25 , in a study involving 232 veterans, considering 17 confounding variables, observed that SBP was not associated with a decline in glomerular filtration when the appropriate adjustments were made.However, the authors observed a strong association between 24-hour ABPM SBP and proteinuria.In addition, the dipper pattern generally decreased as the stage of CKD progressed, albeit not in a linear manner.In our study, the non-dipper pattern was associated with a decline in glomerular filtration rate, i.e. with more advanced stages of CKD (stages 2, 4 and 5), consistent with expectations based on literature evidence 26,27 .In our study, patients in stages 3b and 5 showed an association with lower and higher SBP, respectively.It is interesting to note that the study by Agarwal & Andersen did not include dialysis patients (stage 5) 25 .
BP variability in chronic kidney patients is increased, which is believed to occur due to a malfunction of baroreceptors and uncontrolled balance between sympathetic and parasympathetic activity 28 .Timio et al. 29 , in a prospective study from 1993, observed that blood pressure variability in renal patients was higher than in controls.In our study, when performing generalized linear regression, the SBP coefficient of variation was only associated with the more advanced stages of CKD (stages 3a, 4 and 5), whereas for DBP, no association was observed at any stage of the studied disease.
Paradoxically, in the present study, the accuracy of office blood pressure measurements was not linked to more severe CKD staging.This finding holds even when considering both old and new classifications for masked hypertension and whitecoat hypertension, which address the use of nighttime and daytime ABPM blood pressures differently.We believe that this discrepancy with the literature 30 is due to a standardized BP measurement performed in our study, reducing possible external interferences such as caffeine consumption, smoking, physical exercise, and negligence regarding resting time before measurement.
We should acknowledge some limitations of this work.The subjects in this study were all from the region of Botucatu, a mid-sized city within the state of São Paulo.Consequently, the demographic sample obtained does not reflect the demographic parameters of Brazil as a whole.We believe this is due to the characteristics of the specific city involved.We also had no means of assessing adherence to AH and CKD treatment, although we were aware of each patient's therapeutic regimen.Another limiting factor in this study was that, although we had the qualitative urine test assessed by Urinalysis, we did not collect data on quantitative proteinuria from a substantial number of patients, which prevented a complete KDIGO 2012 classification.Finally, the prevalence of masked hypertension may have been underestimated, considering that in this study, ABPM was not systematically performed on all chronic kidney disease patients with normal office blood pressure, but only on those who underwent ABPM at our institution.Conversely, the same bias could occur among patients who did not present with CKD in our sample, which could balance the biases.
We can also highlight positive aspects of the current study that have not yet been explored in literature.Firstly, since this was a cross-sectional study, we were able to encompass a large sample of 851 patients with good representativeness across the different stages of CKD.A review of the literature revealed a paucity of studies that have conducted such a comprehensive analysis of ABPM parameters in conjunction with different stages of CKD.Furthermore, few studies have considered confounding variables when analyzing their data.

conclusIon
In our sample, more advanced stages of CKD were associated with reduced nocturnal dipping and greater blood pressure variability.Elevations in SBP and DBP were only observed in stage 5. Conversely, the decrease in 24-hour SBP was associated with an intermediate CKD stage (stage 3b), even considering confounding factors.Paradoxically, the accuracy of office-measured blood pressure was not associated with more advanced stages of CKD.
In this context, the current study encompassed a larger number of patients and data for analysis, as well as a detailed assessment of the relationships between different stages of CKD and the main specific characteristics of ABPM, while considering potential confounding factors.
This allowed us to properly explore how the different stages of CKD are associated with the parameters of ABPM examination.

Figure 2 .
Figure 2. Box plot of the distribution of antihypertensive drugs across different stages of chronic kidney disease.